HEMA2 - Secondary Hemostasis Flashcards by Joy Christelle

Coagulation is a process whereby, on ___, ___, ___, ___ interact on the surface of platelets to form fibrin clot.

Vessel injury
Plasma proteins
Tissue factors
Calcium

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___ formed in primary hemostasis and ___ formed in secondary hemostasis

Platelet plug
Fibrin

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4 COAGULATION FACTORS

1 - Found in plasma
2 - Synthesized in the liver except for Factor III and IV
3 - They circulate in the blood in an inactive form except calcium and thromboplastin
4 - Activated only when needed

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The year when the INTERNATIONAL COMMITTEE FOR STANDARDIZATION OF THE NOMENCLATURE OF THE BLOOD CLOTTING FACTORS name the coagulating factors:

1958

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There are ___ coagulation factors, which are
interdependent.
List them all.

14
I, II, III, IV, V, VII, VIII, IX, X, XI, XII, XIII, PK, HMWK

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor I

-Fibrinogen
-None
-Fibrin Clot

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor II

-Prothrombin
-Prethrombin
-Serine protease

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor III

-Tissue Factor
-Tissue Thromboplastin
-Cofactor

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor IV

-Calcium
-None
-Already an active form

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor V

-Proaccelerin
-Labile factor / Accelerator globulin
-Cofactor

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor VII

-Proconvertin
-Stable factor / Serum Prothrombin Conversion Accelerator (SPCA) / Autoprothrombin I
-Serine protease

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor VIII

-Anti hemophiliac Factor A
-Anti hemophiliac globulin / Platelet Cofactor I
-Cofactor

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor IX

-Plasma Thromboplastin Component (PTC)
-Anti hemophiliac Factor B / Christmas Factor / Platelet Cofactor 2
-Serine protease

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor X

-Stuart Prower Factor
-Autoprothrombin II
-Serine protease

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor XI

-Plasma thromboplastin Antecedent (PTA)
-Anti hemophiliac C
-Serine protease

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor XII

-Hageman Factor
-Glass factor / contact factor
-Serine protease

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Give the

Preferred name:
Synonyms:
Active form / function:

of Factor XIII

-Fibrin Stabilizing Factor
-Laki lorand Factor / Fibrinase / Fibrinoligase / Phase transglutaminase
-Transglutaminase

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Give the

Synonyms:
Active form / function:

of Prekallikrein

-Fletcher factor
-Serine protease

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Give the

Synonyms:
Active form / function:

of High Molecular Weight Kininogen

-Fitzgerald factor
William factor
Flaujeac factor
Contact activation cofactor
-Cofactor

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PK AND HMWK does not have assigned roman numerals because they belong to:

kallikrein and kinin system

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Molecular weight of

FACTOR I (FIBRINOGEN)
FACTOR II (PROTHROMBIN)
FACTOR V (PROACCELERIN)
FACTOR VII (PROCONVERTIN)
FACTOR VIII (ANTI-HEMOPHILIC A FACTOR)
FACTOR IX (ANTI-HEMOPHILIC B FACTOR)
FACTOR X (STUART-PROWER FACTOR)
FACTOR XI (ANTI-HEMOPHILIC C FACTOR)
FACTOR XII (CONTACT FACTOR)
FACTOR XIII – FIBRIN STABILIZING FACTOR

HIGH MOLECULAR WEIGHT KININOGEN (HMWK)

PREKALLIKREIN (PK) (FLETCHER FACTOR)

I - 341,000
II - 63,000
V - 300,000
VII - 60,000
VIII - 1,000,000
IX - 62,000
X - 58,900
XI - 160,000
XII - 80,000
HMWK - 120,000
PK - 85,000

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Factor I / Fibrinogen:
Normal value in plasma

200 - 400 mg/dl

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Purpose of Factor I / Fibrinogen

Upon exposure to thrombin, it will form fibrin

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Factors manufactured in the liver / Produced in the liver

FACTOR I (FIBRINOGEN)
FACTOR II (PROTHROMBIN)
FACTOR V (PROACCELERIN)
FACTOR VII (PROCONVERTIN)

FACTOR IX (ANTI-HEMOPHILIC B FACTOR)
FACTOR X (STUART-PROWER FACTOR)
FACTOR XI (ANTI-HEMOPHILIC C FACTOR)
FACTOR XII (CONTACT FACTOR)
FACTOR XIII – FIBRIN STABILIZING FACTOR
HIGH MOLECULAR WEIGHT KININOGEN (HMWK)
PREKALLIKREIN (PK) (FLETCHER FACTOR)

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Half-life of FACTOR I (FIBRINOGEN) FACTOR II (PROTHROMBIN) FACTOR V (PROACCELERIN) FACTOR VII (PROCONVERTIN) FACTOR VIII (ANTI-HEMOPHILIC A FACTOR) FACTOR IX (ANTI-HEMOPHILIC B FACTOR) FACTOR X (STUART-PROWER FACTOR) FACTOR XI (ANTI-HEMOPHILIC C FACTOR) FACTOR XIII – FIBRIN STABILIZING FACTOR HIGH MOLECULAR WEIGHT KININOGEN (HMWK)

I --> 3-4 days II --> 60 hours V --> 12-14 hours VII --> 4-6 hours VIII --> 12 hours IX --> 24 hours X --> 40 hours XI --> 45 hours XIII --> 3-5 days HMWK --> 6.5 days

Factors active in A) intrinsic and extrinsic pathway: B) intrinsic pathway C) extrinsic pathway

A* FACTOR I (FIBRINOGEN) FACTOR X (STUART-PROWER FACTOR) FACTOR XIII – FIBRIN STABILIZING FACTOR B* FACTOR VIII (ANTI-HEMOPHILIC A FACTOR) FACTOR IX (ANTI-HEMOPHILIC B FACTOR) C* FACTOR III (THROMBOPLASTIN)

Purpose of FACTOR II (PROTHROMBIN)

When exposed to V, Xa, PF3, and Ca++, it is converted to thrombin

Factors that are vitamin K dependent

FACTOR II (PROTHROMBIN) FACTOR VII (PROCONVERTIN) FACTOR IX (ANTI-HEMOPHILIC B FACTOR) FACTOR X (STUART-PROWER FACTOR)

2 portions of FACTOR II (PROTHROMBIN)

1. Pro-portion (Fragment 1.2) – responsible for the binding the prothrombin molecule 2. Thrombin portion (Prethrombin 2)

lipoprotein found in tissue: what factor?

FACTOR III (THROMBOPLASTIN)

FACTOR III (THROMBOPLASTIN) are Exceptionally high concentrations are found in the ___ and ___

brain lungs

Factor with no enzymatic activity

FACTOR III (THROMBOPLASTIN)

Required in the several steps in coagulation pathway: what factor?

FACTOR IV (IONIZED CALCIUM)

Precursor to a cofactor that speeds the transformation of prothrombin to thrombin: what factor?

FACTOR V (PROACCELERIN)

It is the most unstable factor and deteriorates rapidly at room temperature: what factor?

FACTOR V (PROACCELERIN)

Activated by tissue thromboplastin: what factor?

FACTOR VII (PROCONVERTIN)

Two functional subunits of FACTOR VIII (ANTI-HEMOPHILIC A FACTOR):

1. VIII:C – procoagulant 2. VIII:vWF (VIII:Ag and VIII:R)

* (Large portion) VIII:vWF is produced in ___ and ___; * (Small portion) VIII:C production site in ___ of the liver

* endothelial cells & platelets * Kupffer cells

___ (Related antigen) is the antigenic portion of the molecule capable of stimulating antibody production and measured by immunoassays Factor VIIIR:RCo (___) demonstrates ristocetin cofactor activity and is important in platelet aggregation

VIIIR:Ag Related Ristocetin

Acts as a carrier for the coagulant portion of the Factor VIII complex; constitutes greater that 90% of this complex

VON WILLEBRAND FACTOR

VON WILLEBRAND FACTOR is synthesized in the ___ and ___ and present in the α granules of the platelets

endothelium & megakaryocytes

Deteriorates rapidly in stored plasma like factor V

Factor VIII

Abnormalities of Factor VIII are the most common hereditary coagulation disorders (e.g., ___ and ___)

hemophilia A & von Willebrand disease

FACTOR X (STUART-PROWER FACTOR) Activated form acts with ___, ___, and ___ to form active thromboplastin

V Ca++ PF3

- One of the contact factors of the intrinsic system - High Molecular Weight Kinninogen (HMWK) is needed as a cofactor with XII for its activation

FACTOR XI (ANTI-HEMOPHILIC C FACTOR)

FACTOR XII (CONTACT FACTOR) Contact factor in the intrinsic system – activated by negatively charged substances such as exposed ___. In vitro, it is activated by ___.

collagen glass

Three functions of XIIa (which are aided by cofactor HMWK):

1. Activate XI 2. Converts prekallikrein (PK) to kallikrein 3. Activates plasminogen in the fibrinolytic system

A deficiency of Factor ___ is the ONLY factor deficiency that causes no coagulation problems

XII

Necessary to form a stable clot – causes crosslinking of fibrin monomers: what factor?

FACTOR XIII – FIBRIN STABILIZING FACTOR

2 functions of HMWK

1. Acts as a cofactor with Factor XII to: a. Activate Factor XI b. Convert prekallikrein (PK) to kallikrein c. Activating plasminogen 2. Converted to kinins by kallikrein which cause: a. Inflammatory reactions b. Pain

5 functions of PK:

a) When converted to kallikrein by Factor XII it then loops back and accelerates the activation of larger amounts of Factor XII b) Converts HMWK to kinins c) Activates plasminogen d) Activates the complement system e) Acts as a chemotactic factor to attract macrophages

4 COAGULATION FACTORS

Substrate Zymogen / enzyme precursor Cofactor Calcium

When zymogens/enzyme precursors (inactive form) are converted into enzymes (active form) they become ___ or ___

SERINE PROTEASES TRANSGLUTAMINASE

3 PHYSIOLOGIC FUNCTIONS OF PROCOAGULANTS

COFACTORS SERINE PROTEASE TRANSGLUTAMINASE

COFACTOR + SERINE PROTEASE = ___ AND ___

STABILITY REACTIVITY

Proteolytic enzymes of trypsin family that activates other specific factors in the coagulation sequence

SERINE PROTEASE

___ is the only substrate in the cascade that does not become an activated enzyme because it is the only ultimate product of clot form

Fibrinogen

Catalyzes the transfer of amino acid in gamma chains of fibrin polymer

TRANSGLUTAMINASE

3 PHYSICAL PROPERTIES OF PROCOAGULANTS (FUNCTIONAL GROUPS)

FIBRINOGEN GROUP PROTHROMBIN GROUP CONTACT GROUP

Consumed in coagulation (they are present in plasma but not in aged serum)

Fibrinogen Group

Have the highest MW of all of the factors

Fibrinogen Group

Most labile group: FIBRINOGEN GROUP PROTHROMBIN GROUP CONTACT GROUP

Fibrinogen Group

Factors included in Fibrinogen Group:

1, 5 + 8 = 13

Synthesized in the liver in the presence of Vitamin K

PROTHROMBIN GROUP

Inhibitors of Vit K:

a) Dietary Vit K Deficiency b) Antibiotics that sterilize intestinal tract c) Oral anticoagulant therapy

Prothrombin Group is not consumed during clotting except factor ___, therefore FVII, IX and X are present in plasma and serum

PROTHROMBIN GROUP is precipitated with ___ (absent in the “adsorbed plasma”)

barium sulfate

Factors included in Prothrombin Group:

2+ 7 = 9, 10

Factors included in Contact Group:

XI, XII, HMWK, PK

Contact Group requires negatively charged particle/substrate (in vivo: ___; in vitro: ___)

collagen kaolin/glass tube

CONTACT PROTHROMBIN FIBRINOGEN Vit. K dependent:

No Yes No

CONTACT PROTHROMBIN FIBRINOGEN Adsorbed by BaSO4 or Alum. hydroxide

Partially Yes No

CONTACT PROTHROMBIN FIBRINOGEN Consumed in coagulation

Partially No except II Yes

CONTACT PROTHROMBIN FIBRINOGEN state other characteristics

Fairly stable Heat labile VII, IX, X are reduced by oral contraceptives Storage labile (V and VIII) Acute phase reactant

Peptides of low MW composed of amino acids

Kinin

PK (___ – activated form) Kininogen (___,___) Kinin (___)

kallikrien LMWK, HMWK bradykinin

COAGULATION & THE KININ SYSTEM play roles in:

1. Intrinsic coagulation activation 2. Activation of fibrinolysis 3. Kinin formation 4. Complement system activation

COAGULATION & THE COMPLEMENT SYSTEM Function:

Lyse antibody coated cells

COAGULATION & THE COMPLEMENT SYSTEM ___ activates C1 which will cleave C3 to C3a and C3b

Plasmin

COAGULATION & THE COMPLEMENT SYSTEM C1 inactivator inhibits ___, ___, ___, ___ and ___

complement activation XIIa XIa plasmin kallikrein

3 THEORIES OF BLOOD COAGULATION :

MORAWITZ THEORY, 1905 HOWELL’S THEORY CASCADE/WATERFALL THEORY, 1964

PT + CA++ + Thromboplastin = Thrombin Fibrinogen + Thrombin = Fibrin (blood clot) What theory?

MORAWITZ THEORY, 1905

1. Prothrombin is inactivated by antiprothrombin (heparin) 2. Thromboplastin neutralizes antiprothrombin and releases prothrombin 3. PT + Ca++ = Thrombin 4. Thrombin + Fibrinogen = Fibrin clot What theory?

HOWELL’S THEORY

* Widely accepted until now * Extrinsic is an old name according to Henry’s * It involves 3 Pathways: What theory?

CASCADE/WATERFALL THEORY, 1964

3 Pathways According to Cascade / Waterfall Theory:

1 - Extrinsic / Tissue Factor Pathway 2 - Intrinsic / Contact Activation Pathway 3 - Common Pathway

Pathway is activated by the release of tissue thromboplastin into the plasma from injured tissue cells

Extrinsic/Tissue Factor Pathway

Pathway is activated by exposure of contact factors to the subendothelium (collagen). “Intrinsic” because all components are found in circulating blood

Intrinsic/Contact Activation Pathway

Pathway begins with the activation of Factor X by either intrinsic/extrinsic pathways

Common Pathway

3 ENZYME COMPLEXES * Factor VIIa + Tissue Factor complex --> VIIa/TF/Ca = activates Factor __ and Factor __ * Factor IXa + Factor VIIIa +Ca + PL complex --> “___ complex” --> IXa/VIIIa/Ca/PL = activates additional Factor X * Factor Xa + Factor Va + Ca + PL complex --> “___ complex” --> Xa/Va/Ca/PL = activates prothrombin to thrombin

* X and IX * tenase * prothrombinase

EVENTS THAT HAPPEN IN THE EXTRINSIC PATHWAY:

* When there is tissue trauma or injury, the extrinsic pathway is activated by releasing tissue thromboplastin (Tissue Factor). * Tissue factor activates factor VII and it converts to activated factor VII, (VIIa). * VIIa combines with Tissue factor in the presence of calcium ions and activates factor X, and it converts to (Xa)

EVENTS THAT HAPPEN IN THE INTRINSIC PATHWAY:

* Injury or exposure of blood to collagen causes the activation of Factor XII to XIIa (partially) with the help of co-factor the HMWK (converts PK to K). * XIIa, acts on factor XI and causes its activation to XIa * XIa, acts on Factor IX and activates to IXa * IXa with factor VIIIa, combines with calcium ions and phospholipid (tenase complex) causes the activation of factor X to Xa

EVENTS THAT HAPPEN IN THE COMMON PATHWAY:

* Xa, in the presence of calcium ions, Factor Va and Phospholipid forms the Prothrombin Activator (Prothrombinase complex) will activate Prothrombin (Factor II) to Thrombin * Thrombin acts on Fibrinogen to form a Fibrin monomer * Fibrin monomer cannot form a clot so, Fibrin Stabilizing Factor or Factor XIII, helps the Fibrin monomer to form a FIBRIN MESH * Fibrin mesh attracts the platelets, phospholipids and etc., and forms a stable fibrin clot

OTHER COMPONENTS OF COAGULATION

* Regulatory factors: Protein C and S * Physiologic inhibitors: - AT III, complement I-inhibitor - Alpha2-macroglobulin, alpha1-antitrypsin, - Plasminogen activators, plasminogen activator inhibitors,TFPI

3 STAGES OF COAGULATION

Stage I – Generation of Thromboplastin Activity Stage II – Formation of Thrombin Stage III – Formation of Fibrin clot

COMPONENTS OF EXTRINSIC PATHWAY

* Factor VII – short half-life * Factor III/Tissue factor – found in lung, brain, placenta, etc

COMPONENTS OF INTRINSIC PATHWAY

* Factor XII * Factor XI * Factor IX * Factor VIII * HMWK * Prekallikrein

COMPONENTS OF THE COMMON PATHWAY

* Factor X * Factor V * Factor II * Factor I * Factor XIII

___ Pathway * In vivo activation – damaged vascular endothelium * In vitro activation – exposure of coagulation factors to negatively charged surface such as glass

Intrinsic

___ Pathway * In vivo – release of TF from damaged tissue * In vitro – addition of tissue extract (PL) to samples

Extrinsic

___ bind to phospholipid (PF3) surface until enzyme, substrate and cofactor is formed

Clotting factors

Final product is a ___ or clot which completely stops bleeding

fibrin mesh

Extrinsic: a) activated upon release of ___ b) Factor ___ and ___ Intrinsic: a) activated upon exposure to ___ b) Factors: Common: a) activated by ___ b) Factors:

thromboplastin III and VII collagen VIII, IX, XI, XII, PH HMWK both pathways I, II, V, X

___ is the physical manifestation of fibrin formation which represents the end result of a series of reactions of coagulation factors (plasma proteins) a.k.a. clotting factors, plasma factors, pro-coagulants, coagulation proteins

Visible coagulum